A defective protein causes a disease!

It is obvious now that defects in proteins, normally because of mutations in the DNA, cause many diseases, but it was not so evident in 1949.
Linus Pauling and his collaborators knew that only deoxygenated blood contains the sickle shaped erythrocytes (see picture) characteristic of sickle cell anemia, which lead them to the hypothesis that hemoglobin was involved in this problem.
They showed that hemoglobin from patients suffering from sickle cell anemia is different (has different electrophoretic mobility) to the “healthy hemoglobin”. In addition, they found that people with sicklemia, a less severe version of the disease, contain both forms of the protein. This was proof of a change in a protein causing a disease!
More important that the actual experiment, are the conclusions derived of it. Not only this was the beginning of “molecular medicine”, but the genetic discussion in the paper is groundbreaking.
Image credit
More about it

How the genetic code was cracked

some possible 3-letter codes
The structure of DNA, solved in 1953, set off a race to crack the genetic code. How do sequences of 4 nucleotides code for sequences of 20 amino acids? This coding problem lies at the heart of molecular biology. Physicist George Gamow of Big Bang fame contributed the first guess: Spaces between neighboring nucleotides might fit individual amino acids, directly templating protein assembly on the DNA. In Gamow's solution, each nucleotide must contribute to defining two amino acids–an overlapping code. The numerology looked good (there were exactly 20 possible combinations), but Gamow's solution turned out to be wrong: In 1957, Sydney Brenner devised a simple test that disproved this and all overlapping triplet codes. The true code was soon cracked based on beautiful frameshift experiments by Crick et al., and by analysis of proteins synthesized from artificial RNAs.
Supplements: Gamow's guess, Brenner disproves Gamow and all overlapping triplet codes, the decisive artificial RNA experiments

How nerves find their targets: Fishing for survival signals

Rita Levi-Montalcini (photo credit)
In 1949, Rita Levi-Montalcini noticed something unexpected. Her colleague Elmer Bueker had found that nerves would invade tumors that he had implanted into chick embryos. What attracted the nerves to tumors? Indeed, how did nerves ever find their normal targets? Levi-Montalcini noticed that the nerves would also invade tissues near the implanted tumors–suggesting that tumors might be releasing a diffusible nerve growth factor, a postulated substance that could guide either nerve differentiation, growth or survival. Levi-Montalcini proved the existence of a nerve growth factor by culturing just tumors and ganglia in the same dish, finding that the nerves from the ganglia would connect to tumors even outside of embryos. Later, she purified the key protein, now called Nerve Growth Factor (NGF). NGF told us that the way nerves find their targets is unexpectedly adaptive–nerves grow just about everywhere, and they die off if they fail to find targets. 
A short review: Aloe, L. (2004) Rita Levi-Montalcini: the discovery of nerve growth factor and modern neurobiology. Trends Cell Biol 14:395-9. 

Some amazing historical background: An excerpt about her pre-NGF work done in makeshift home labs she set up hiding out in the hills during WWII, from her autobiography, In Praise of Imperfection. Open the excerpt in the right pdf viewer and you'll see some helpful notes in red.

Evolution in action: Darwin's finches

Since the publication of Darwin's "On the Origin of Species", we have had an outline for how evolution can occur by natural selection. There must be variation in a trait between individuals, that variation must be heritable, and more individuals must be produced than can survive and reproduce.  Natural selection can then act on that variation, leading to changes in population frequencies of the trait value. Theoretically, this scheme makes sense, but empirically it is difficult to observe, since evolution acts over large time scales.  Enter Peter and B. Rosemary Grant. The Grants went back to Darwin's birds, the Galapagos finches, to try to peek at evolution in action. Beginning in 1976, they and their students spent months of every year in the Galapagos, measuring everything they could about the finches and their habitat. Then, between 1982 and 1983, the most extreme El Nino event in 400 years occurred, and the Grants finally got their chance. Their 1993 paper reports their findings.
Additional: "Ecology and the Origin of Species"

The random origin of mutations versus directed mutations

Luria & Delbrück in 1941.
Original repository:
Cold Spring Harbor Laboratory Archives
Do mutations arise randomly with respect to their fitness effects (undirected mutations), or do organisms acquire mutations that are favorable upon exposure to a new environment (directed mutations)? Most of our current knowledge of evolution and genetics relies on undirected origin of mutations. The Central Dogma, as we know it now, wouldn’t exist if mutations were directed. The question remained largely unanswered until 1943, until Salvador Luria and Max Delbrück conducted an experiment, which, along with their subsequent work, won them the Nobel prize in 1969. This was before DNA was identified as the carrier of genetic information, and we still didn’t know whether prokaryotes and eukaryotes used the same genetic material. The experiment was a brilliant integration of simple microbiology, probability theory and a phylogenetic context. Surprisingly, the experiment used little more technology beyond plating out E. coli with a bacteriophage and counting how often resistant bacterial mutants arose.
 A "recent" review by Lenski & Mittler about the reignited directed mutation controversy. Gives a good summary of the Luria-Delbrück experiment too. - http://lenski.mmg.msu.edu/lenski/pdf/1993,%20Science,%20Lenski%20&%20Mittler.pdf

Why do we sleep?

Xie et al, 2013.
The question of why animals sleep is one that has gone unanswered for many years. However, new findings have shed light on a possible evolutionary reason for the restorative function of sleep. Using in vivo imaging techniques, researchers at the University of Rochester have found that during sleep the cerebrospinal fluid interchanges with the interstitial fluid of the brain. It then circulates throughout the brain to remove metabolic waste products that form due to neuronal activity. Neurons are especially sensitive to their environment and removal of waste products is thought to prevent cellular damage. One such product, β-amyloid, negatively affects synaptic transmission, and its accumulation is thought to be associated with Alzheimer’s disease. This study showed that during sleep β-amyloid is removed from the brain significantly faster than during waking hours. The findings of this paper are likely to impact sleep and disease research for years to come.
The role of amyloid β in the pathogenesis of Alzheimer's disease.

DNA vs. Protein: who carries the genetic information?

Photo credit
Even though DNA was discovered in 1869, most scientists assumed that proteins carried heritable information. The Avery-MacLeod-McCarty experiment (1944) suggested that DNA was the genetic material, but the general scientific community hesitated to accept this. DNA was thought to be far too simple to contain the complex nature of inheritance, while proteins were thought to be complex enough to carry the genetic information. It wasn’t until the results of the elegantly-designed experiment conducted by Alfred Hershey and Martha Chase were published in 1952 that everyone had to acknowledge that DNA was the hereditary molecule. This experiment was so simple and elegant that no one could argue with the straightforward conclusion.
Avery-MacLeod-McCarty paper that set the stage

Experimental tests of evolution in the lab and field

In evolutionary biology, we often have to let nature do our experiments for us because evolution is thought to act over time scales too large to observe in the confines of an experiment, especially in vertebrates.  However, John Endler changed that idea with his work on guppies in the streams of Trinidad.  There, guppy coloration patterns are subject to sexual selection via mating preferences and natural selection via predation.  Along the streams, waterfalls divide different pools, and those pools have different levels of predation on guppies.  Endler took advantage of this natural experimental setup and transplanted guppies from higher predation pools to lower predation pools to test predictions about the evolution of their coloration under different selective regimes.  He was able to confirm his hypothesis that under lower predation, guppy coloration would evolve away from crypsis (advantageous under high predation) to more complex and colorful patterns (advantageous for mating).

The First Biological Gears Discovered!

Video (made into a GIF) from
the paper supplemental materials
There's been some talk about living organisms and the use of biological gears, and frankly, how there isn't any known in nature. They seem like a perfect system to move different things simultaneously, yet it looked like nothing had evolved it. Until a September 13th issue of Science, that is. Malcolm Burrows and Gregory Sutton wanted to know how planthopper nymphs were able to jump well and straight every time. They first looked at the back leg joints, and noted how synchronous the legs moved (and moved within 30 microseconds of each other!). Upon microscopy they noted the biological gears, and characterized the cocking and release mechanisms of the legs used to jump. Isn't nature awesome?!
Supplemental News Article with videos: http://www.popularmechanics.com/science/environment/the-first-gear-discovered-in-nature-15916433

Suspended animation: saving time on the way to deep space and the hospital

"Alien" (1979)
Suspended animation is a process where an organism’s physiological processes slow down to a point resembling death. Several species have been documented to undergo suspended animation during early development when in the complete absence of oxygen and/or freezing cold. Mimicking torpor and hibernation, animals under suspended animation display near halted metabolic rates with concomitant drop in heart rate, brain activity, and overall cellular activity. Upon re-exposure to oxygen and/or rewarming, physiological processes start up again and the organism lives out a normal lifespan. The applications for suspended animation in humans are far spanning from deep space exploration with living astronauts to saving the lives of victims of severe trauma. Furthermore, the means by which suspended animation can be induced with high survival rates during re-emergence is relatively simple and can be induced via several methods. In 2005, researchers in Seattle discovered the use of hydrogen sulfide gas in inducing suspended animation and were able to successfully place mice in near metabolic arrest for 6 hours with normal exit. This was the first time a mammal was successfully suspended and suggests it could be extended to humans.
  • The incredibly brief Science paper
A very recent and awesome paper on suspended animation

Experimental replication of a hybrid speciation event

Helianthus anomalus  (credit)
What makes a new species?  A difficult question, especially given the nature of the speciation continuum.  Loren Rieseberg and colleagues used a hybrid species complex, Helianthus annuus and H. petiolaris and their hybrid species, H. anomalus, to study the genetic architecture of hybrid species formation.  They experimentally generated hybrids of H. annuus and H. petiolaris and compared the genomes of those experimental hybrids to the ancient hybrid species, H. anomalus.  They found that the genome of the hybrid species is not a random mash-up of the parental genomes but instead is constrained by the interactions between the parental genes.  The hybridization event itself may have been a random occurrence, but the genetic composition of the resulting species was anything but random.

Evolving multicellularity in the lab

from Ratcliff et al., 2012
One of the biggest milestones in the evolution of the complex life that exists today was the formation of multicellular organisms. This major transition permitted an increase in the size of organisms as well as an opportunity for division of labor among cooperating cells. Using the unicellular yeast, S. cerevisiae, Ratcliff et al. selected for multicellularity by centrifugation. With this strategy larger yeast are more likely to be transferred to the next culture. Within 60 days yeast formed elaborate multicellular structures that produced multicellular progeny. The authors also observed a division of labor among cells. While early multicellular organisms were physiologically similar, later organisms showed an increase in programmed cell death. This experiment demonstrates the rapidity with which multicellular evolution can occur given the correct selective environment.
A news article explaining the findings

Silly science and frivolous funding: The history of statins

Akira Endo
Nature Medicine (2008)
Government funding of scientific research is often a targeted due to publicized ‘weird science.’ Yet, ‘weird scientists’ are behind several of the most important medical breakthroughs of our time! One such example include statins, a group of drugs commonly prescribed to treat high cholesterol. Over half of all American men and more than 2 in 5 American women over the age 65 take statins (National Center for Health Statistics, Health, United States, 2012).

Their unlikely origin: Fungi.

Dr. Akira Endo discovered the first statins in a screen searching for inhibitors of cholesterolgenesis from chemical compounds derived from Penicillium citrinum in the 1970s.  Three of the 6000 compounds tested reduced cholesterol synthesis in a rat liver enzyme model. (Talk about successful drug discovery!)  Today, statins remain the subject of ongoing research in the prevention of dementia, reduction of inflammation, and treatment of cancer and stroke.

An extra--Statins and diabetes risk: Risk of incident diabetes among patients treated with statins: population based study. 

An NPR report detailing a recent 'weird science' controversy (worth a listen!):  'Shrimp On A Treadmill': The Politics Of 'Silly' Studies

Stay calm: Stress fuels cancer metastasis


It has been noticed that breast cancer patients who suffer from stress and depression following the primary treatment tend to have higher rates of relapse, metastasis and death. Even though this observation has been confirmed in mice, the mechanistic link between stress and metastasis is still unknown. Campbell et al. beautifully put the whole picture together. They proved that stimulation of the sympathetic nervous system in mice, a consequence of chronic stress and depression, promotes breast cancer cells to metastasize to bone by changing the bone marrow microenvironment. Under stress condition, the level of cytokine RANKL is increased in host bone marrow stroma, which enhances bone breakdown and makes the colonization of breast cancer cells in bone easier. Most importantly, the metastasis can be reduced by blocking the effects of stress, suggesting a new therapeutic strategy to prevent breast cancer metastasis–reducing stress in patients. 
Extra: Is living better equal to living longer?

To necrose or simply apoptose

 Endochondral ossification of developing vertebrae.
University of New South Wales, Cell Biology.
The term ‘cycle of life’ elicits imaginings of birth, growth and development, reproduction, and of eventual death. Yet, the ‘cell cycle’ is a term used to typically only refer to the process of cellular division and replication.  In fact, programmed cell death was first described even before the process of cellular division. In 1842, Karl Vogt noticed that the notochord of the midwife toad was replaced by vertebrae during development and suggested this was due to cellular reabsorption followed by replacement by nearby cartilage cells.  His research, which set the foundation for the field of apoptosis, was not followed up until much later.  In the century following, most research focused on bone ossification or the cellular death that occurs in metamorphic insects and amphibians during maturation (for example, loss of the tadpole tail and gills, and the changes that occur in flies during pupation). Unfortunately, most of this early research was all published in French and German, and therefore inaccessible for this platform. However in the field of apoptosis, another integral work published in 1965 by John Kerr distinguishes programmed cell death and traumatic cellular death. Kerr described unique histological changes in rat liver after portal vein ligation injury, which he called ‘shrinkage necrosis’ before later coining the term ‘apoptosis.’

This seems long, but as most of it is histology images it is a fairly quick read:

An interesting history summarizing early apoptosis research that I found useful:
P.G. Clarke & S. Clarke (2012). "Nineteenth century research on cell death." Exp. Oncol., 34: 139-145.

For the polyglot: K.C. Vogt (1842). "Untersuchungen über die Entwicklungsgeschichte der Geburtshelferkröte (Alytes obstetricans)." Solothurn: Jent und Gassmann.

After 40 years the mysterious function of telomeres was solved

Telomeres (yellow)
 www.michaelwest.org, used with permission
The scientific community knew about telomeres for ~40 years before its role of chromosome protection was determined by Blackburn and Szostak. In the 1930s, both Muller, who gave telomeres their name, and McClintock hypothesized that telomeres protect chromosomes, but without the appropriate molecular techniques the field lost interest. Blackburn, who had found short repeating DNA in telomeres, presented her data at a conference in 1980. Szostak was working with linear DNA or "minichromosomes" in yeast that degraded rapidly, and after hearing Blackburn's research became interested in collaborating. In a simple experiment, they attached Blackburn's telomeric DNA to Szostak's minichromosomes and were excited when they noticed the minichromosomes were protected from degradation. Blackburn and her graduate student Greider went on to discover telomerase and ultimately earned all three the Nobel Prize in 2009. Learning the function of telomeres and how they are synthesized has opened the doors to aging and cancer research.
An optional article about Blackburn: Natural History Blackburn article

Glowing in a sea of darkness (discussed by the group on 10/23/13)

An image of the brain stem whereby different
structures are expressing different fluorescent
proteins to demonstrate the formation of
synapses between axons and neurons.  Photo Credit
The 20th century marked a vast development in the fields of genetics and biochemistry. During this time the structure of DNA was uncovered, enzyme function could be assessed through crystallography and NMR, and whole genome sequencing was being developed. With these advancements, however, there was still no mode of tracking the location of proteins or monitoring the cellular processes of proteins in a living system. The discovery of the green fluorescent protein (GFP), however, opened the doors for monitoring and viewing proteins in a cell. Osamu Shimomura first identified GFP in 1962 when he isolated the bioluminescent protein from the jellyfish, Aequorea victoria. It wasn't until 1994, however, when Martin Chalfie demonstrated the utility of GFP as a fluorescent marker. This discovery would later earn him a Nobel Prize alongside Shimomura. The ubiquitous use of fluorescent proteins in laboratories worldwide undoubtedly demonstrates the impact of this discovery.

Darwin's "warm little pond": the Miller-Urey experiment (discussed by the group on 10/9/13)

The scientific community’s eventual acceptance of natural selection as the driver of diversity of life-forms opened many lines of inquiry, including the origin of life and how complex organic molecules required for life could possibly form from simpler inorganic chemicals. Darwin himself spoke to friends of a hypothetical primordial soup where this might occur.

In 1953 at the University of Chicago, Stanley Miller and Harold Urey placed several gases (methane, ammonia, and hydrogen) into a closed system with heated water and an electrical spark to simulate lightning storms, conditions thought to be present in early Earth’s atmosphere. Within weeks, >10% of carbon in the experiment was found in the form of organic compounds including amino acids, the building block of proteins. Subsequent experiments have shown that nucleotide bases can also be formed in such conditions, such as adenosine, also the key component of ATP. The original experiment continues today at the University of California San Diego, and its findings have guided the field of abiogenesis, an investigation that’s since been extended to include extraterrestrial sources.
Q: Are ancestral gene products enriched for Miller-Urey amino acids?
A: Yes, yes they are

The microbiome, the human genome, and diet: An emerging story of symbiosis (discussed by the group on 10/16/13)

You are what you eat. You also happen to be what the thousands of other microbes that inhabit your body eat.  Far more important than either one alone is the relationship between you, your microbiome, and your diet, which together influence your risk for certain diseases.  

A recent paper by Wang et al. (2011) is one of the first to show the effects of imbalance in this complex dance resulting in disease risk. Through a metabolomic screen, the formation of atherosclerotic plaques was found to be associated with a metabolite, whose generation requires certain intestinal microbes, a human protein in the liver, and dietary sources of choline such as fish, red meat, eggs, and milk.  The relationship between host genetics, the microbiome, and environmental factors, is emerging as an exciting area of focus in understanding the architecture of complex disease.

The Paper:
See also: Tang, W.H.W. et al. New England Journal of Medicine 368, 1575-1584 (2013).

A schematic showing the three components necessary for TMAO production. Wang et al. (2011) showed that TMAO is highly associated with cardiovascular disease risk. Figure from Rak & Radar, Nature, 472, 40-41 (2011).

Lords of the flies

Drosophila melanogaster
by André Karwath
“Let’s do a screen.” It’s a phrase bandied about in laboratories all over the world from scientists at all stages of their careers. However, the power of genetic screens was not fully realised until the late 1970s, when Christiane Nüsslein-Volhard and Eric Wieschaus performed their famous screen that identified mutations affecting Drosophila developmental patterning.

The first results of the Nüsslein-Volhard and Weischaus screens were published in a Nature paper in late 1980. Despite having incomplete results, the work presented is remarkable in that it identified and categorised a majority of the segmentation patterning genes in Drosophila. In designating different levels of organisation in the developing embryo, this screen helped elucidate our current understanding of development. While it certainly wasn’t the first screen, its scale and breadth laid the groundwork for not only future studies in Drosophila and other models, but arguably started the field of developmental genetics.

In 1984, Nüsslein-Volhard, Wieschaus, and colleagues published the complete results of their screen. These were published in a total of three papers, one for the 2nd chromosome, one for the 3rd, and one for X and the 4th chromosome (the latter of which is vestigial in flies).

Some historical perspective from Wolfgang Driever (a graduate student of CNV) and Janni Nüsslein-Volhard herself

Genes are physical objects located on chromosomes, not theoretical constructs

Fly room at Columbia University
Photo credit
On one random day after thousands of Drosophila crosses, Thomas Morgan came across a fly that had white eyes instead of red. Fascinated, he began crossing the flies, trying to figure out how this mutation arose and if it would be passed on. His discoveries were printed in Science and built a foundation for the modern theory of genes. Interestingly, only one year earlier, Morgan had criticized scientists for believing that genes were located on chromosomes without any hard evidence. Being an adamant believer in hypothesis-driven science, he could now show that genes were located on chromosomes and that some of these genes were sex-linked. Additionally, this data debunked the widely-held notion that mutations immediately gave rise to new species. This paper gave the first hard evidence that genes are located on chromosomes, leading Morgan and his students to eventually make the first genetic map.
And a paper by Morgan's student, Calvin Bridges, proving the theory of chromosome inheritance.

One-way traffic: How are different stages of the cell cycle coordinated?

from Rao & Johnson, 1970
We all originate from a single cell, the fertilized egg, through cell division. Before a cell can divide it has to increase in size, duplicate its DNA and precisely separate the chromosomes into two daughter cells. These processes are coordinated in the cell cycle. Since the process of cell division has been observed, the next big question is how the cell cycle is regulated. In a Nature paper published in 1970, Rao and Johnson discovered an important clue to the nature of cell-cycle regulation by fusing mammalian cells in different phases of the cell cycle. This elegant experiment firstly showed the existence of diffusible dominant factors affecting cell cycle progression. Besides, it provides an insight into the concept of checkpoint controls. Due to this significant observation, the identification of the cell cycle regulators has been a focus ever since.

Cancer resistance in the naked mole rat (discussed by the group on 9/25/13)

Photo credit
The naked mole rat is a highly unusual rodent, with a lifespan of 30+ years despite its small size. In addition to an extended lifespan, naked mole rats are completely resistant to cancer. Mice are widely utilized in cancer research due to both their high cancer rates and relatively short lifespan, but in the quest to discover novel anticancer mechanisms, the Gorbunova and Seluanov labs employed naked mole rats for their studies. They discovered that naked mole rat cells are highly sensitive to contact inhibition, a trait often lost in cancer. It was also observed that media containing naked mole rat cells became much more viscous than that of mouse cells, leading to the discovery of the signaling molecule responsible for naked mole rat cancer resistance: extremely high molecular weight hyaluronan. This discovery and the use of naked mole rats for cancer studies could benefit cancer research for years to come.
Previous work from the same labs presenting the naked mole rat's hypersensitivity to contact inhibition.
News article concerning the discovery published in this paper.

The uncovering of acquired characteristics

Conrad Waddington
In the past two decades, epigenetics has taken the forefront in defining diseases and providing new therapeutic targets. Through DNA methylation, histone modifications and nucleosome remodeling, epigenetics has altered the way we view and study diseases. The idea underlying epigenetics, however, is not novel but dates back to the 1800s. More in-depth analysis, however, was not conducted until the early 1900s when Conrad Waddington proposed the idea of "acquired characters", whereby an organism is able to acquire characters that allow the organism to develop normally in response to different environmental conditions. In this paper Waddington demonstrates his idea of genetic assimilation of characteristics by analyzing the cross-vein in Drosophila melanogaster under a stressed temperature condition. The ideas set forth in this paper and his earlier papers provided the basis of acquired characteristics due to different environmental exposures.
Other Reading: Waddington, 1942

A long way since the discovery of short RNAs

From Wightman, Ha, and Ruvkun, 1993
Since the turn of the current century, much attention has been focussed on microRNAs, a family of small, noncoding RNAs that have critical functions in regulating gene expression in development and disease. In a pair of papers published in Cell in late 1993, members of the Ambros and Ruvkun groups describe the interaction between the essential genes lin-4 and lin-14 in the worm Caenorhabditis elegans. Quite unexpectedly, lin-4 was found to be a small RNA that does not code for a protein product. Additionally, lin-4 was found to target lin-14 at the latter’s 3ʹ UTR, a region that had been thought of as bland and uninteresting. Despite their papers’ impact, the authors never set out to answer questions about noncoding RNAs or gene regulation. They simply wanted to know more about an interesting set of mutants. Perhaps that is what is so great about these experiments.

The papers:
Additionally, here are some reminiscences from the Ambros group and the Ruvkun group. They contain wonderful historical context, and some rather amusing anecdotes about the publication of these papers. A news and views article from Nature that was published about one month after the Cell papers provides some interesting insight into the reception of the groups’ work. There is clear excitement at the possibility of a new class of regulatory RNAs tempered by a dose of scepticism.

An alternative to blending inheritance

Gregor Mendel
Photo Credit
Until the 19th century, a coherent mechanism of trait inheritance from parents to offspring did not exist.  Biologists had long known that children tended to resemble their parents, but lacked a set of laws describing patterns of trait inheritance that could also account for the maintenance of phenotypic variation in subsequent generations.  The most popular idea of the time was a model of blending inheritance, in which the hereditary material of parents is randomly assembled from a range of values present in each individual, giving rise to children with characteristics intermediate between the two parents.  In 1866, Gregor Mendel published an 8-year study on plant hybridization in which he described a pattern of discrete, independent 'factor' inheritance for several polymorphic traits.  Despite being largely ignored for nearly 40 years, this work would eventually become the foundation of classical genetics and prove fundamental to the modern synthesis of evolutionary biology.
More on the historical context of Mendel's work: http://www.strangescience.net/mendel.htm

The accidental discovery of the "miracle drug" penicillin

Penicillin was mass produced during WWII and given to Allied soldiers.
Photo credit: US National Library of Medicine
Before antibiotics, simple bacterial infections ended in death. After a holiday in 1928, Alexander Fleming was cleaning out bacterial plates and found something unusual. He noticed bacteria were dying on one of the plates, but only around a unique mold colony that he later determined to be a fungus in the Penicillium genus. This mold happens to kill not only the genus of bacteria he was growing, Staphylococcus, but luckily for us a variety of other bacteria! Due to the challenge of isolating penicillin, this revolutionary discovery lay dormant for a decade before Ernest Chain and Howard Florey picked up Fleming's work by isolating penicillin, and testing it on mice infected with bacteria. In 1945, they were all awarded the Nobel Prize for the discovery and “its curative effect in various infectious diseases.” Penicillin was heralded a “miracle drug” and continues to save lives today.
The second paper: Penicillin as a chemotherapeutic agent 
The Discovery and Development of penicillin Commemorative Booklet

How did we find out the plasma membrane is a bilayer?

During the late 1800's not much was known about the boundary surrounding cells, except that there was one, and it was probably made of lipids (Overton, 1889). In 1924, Gorter and Grendel wanted to know how lipids surrounding cells were organized. Using red blood cells from mammals (which lack membrane bound organelles) and estimated their surface area. They extracted the lipids from these cells and spread them out into a layer 1 molecule thick. Measuring the area of this monolayer and found it to be almost exactly 2 times greater than the surface area of the cells the lipids had been come from. Their conclusion: if cells are covered in lipids, and there are enough lipids to cover the surface of a cell twice, then cells are actually covered by lipids two molecules thick (a bilayer).
Something extra. A short and interesting primer on the discovery of the lipid bilayer from Nature Education.

Gorter and Grendel used a modified version of a Langmuir Trough to measure the surface area of lipids extracted from mammalian red blood cells.

Source: Nature Education